Cytochrome P-450 CYP1B1 is a dioxin-inducible form of the cytochrome P-450 family of xenobiotic metabolising enzymes. CYP1B1 is expressed at a high frequency in a wide range of human cancers of different histogenetic types and is not expressed (or only at negligible levels) in normal tissues, see, e.g.: McFadyen M C, Melvin W T and Murray G I, “Cytochrome P450 Enzymes: Novel Options for Cancer Therapeutics”, Mol Cancer Ther., 3(3): 363-71, 2004; McFadyen M C and Murray G I, “Cytochrome P450 1B1: a Novel Anticancer Therapeutic Target”, Future Oncol., 1(2): 259-63, 2005; Sissung T M, Price D K, Sparreboom A and Figg W D, “Pharmacogenetics and Regulation of Human Cytochrome P450 1B1: Implications in Hormone-Mediated Tumor Metabolism and a Novel Target for Therapeutic Intervention”, Mol. Cancer. Res., 4(3): 135-50, 2006. More specifically, CYP1B1 has been shown to be expressed in bladder, brain, breast, colon, head and neck, kidney, lung, liver, ovarian, prostate and skin cancers, without being expressed in the corresponding normal tissue.
For example, Barnett, et al., in Clin. Cancer Res., 13(12): 3559-67, 2007, reported that CYP1B1 was over-expressed in glial tumours, including glioblastomas, anaplastic astrocytomas, oligodendrogliomas and anaplastic oligodendrogliomas, but not unaffected brain tissue.
Carnell, et al., in Int. J. Radiat. Oncol. Biol. Phys., 58(2): 500-9, 2004, reported that CYP1B1 was over-expressed in prostate adenonocarcinomas, but not in matched normal prostate tissue.
Carnell et al., 2004 (ibid.) also showed that CYP1B1 is expressed in (n=22, 100%) of bladder carcinomas
Downie, et al., in Clin. Cancer Res., 11(20): 7369-75, 2005 and McFadyen, et al., in Br. J. Cancer, 85(2): 242-6, 2001, reported increased expression of CYP1B1 in primary and metastatic ovarian cancer, but not in normal ovary tissue.
Gibson, et al., in Mol. Cancer. Ther., 2(6): 527-34, 2003, and Kumarakulasingham, et al., in Clin. Cancer Res., 11(10): 3758-65, 2005, reported that CYP1B1 was over-expressed in colon adenocarcionomas as compared to matched normal tissue.
Several studies have shown that CYP1B1 is over-expressed in breast cancer as compared to matched normal tissue. (See, e.g.: Murray G I, Taylor M C, McFadyen M C, McKay J A, Greenlee W F, Burke M D and Melvin W T, “Tumor-Specific Expression of Cytochrome P450 CYP1B1”, Cancer Res., 57(14): 3026-31, 1997; Haas S, Pierl C, Harth V, Pesch B, Rabstein S, Bruning T, Ko Y, Hamann U, Justenhoven C, Brauch H and Fischer H P, “Expression of Xenobiotic and Steroid Hormone Metabolizing Enzymes in Human Breast Carcinomas”. Int. J. Cancer, 119(8): 1785-91, 2006; McKay J A, Murray G I, Ah-See A K, Greenlee W F, Marcus C B, Burke M D and Melvin W T, “Differential Expression of CYP1A1 and CYP1B1 in Human Breast Cancer”, Biochem. Soc. Trans., 24(2): 327S, 1996).
Everett, et al., in J. Clin. Oncology, 25: 18S, 2007, reported that CYP1B1 was over-expressed in malignant melanoma and disseminated disease but not in normal skin.
Gibson, et al., 2003 (ibid.) and Chang, et al., in Toxicol. Sci., 71(1): 11-9, 2003, both reported that while CYP1B1 was not present in normal liver it was over-expressed in stage IV metastasis to the liver.
Greer, et al., in Proc. Am. Assoc. Cancer Res., 45: 3701, 2004, reported that CYP1B1 was over-expressed during the malignant progression of head and neck squamous cell carcinoma but not in normal epithelium.
McFadyen, et al., in Br. J. Cancer, 91(5): 966-71, 2004, detected CYP1B1 in renal carcinomas but not in corresponding normal tissue.
Murray, et al., 2004 (ibid.) used immunohistochemistry to show over-expression of CYP1B1 in lung cancer cells as compared to normal lung tissue.
It is evident from the numerous disclosures cited above that CYP1B1 expression is characteristic of a range of different cancers and other proliferative conditions, and that CYP1B1 expression may be used to define such a range of cancers and other conditions. As normal (non-cancerous) cells do not express significant levels of CYP1B1, it may also be reasonably expected that compounds that exhibit cytotoxicity in cells expressing CYP1B1, but are substantially non-cytotoxic in normal cells, would have utility as targeted anti-cancer agents in cancers characterised by CYP1B1 expression. By “targeted” is meant that such compounds could be delivered systemically and would only be activated in the presence of cancerous cells expressing CYP1B1, remaining substantially non-toxic to the rest of the body.
Further, a number of cytochrome P450 enzymes are known to metabolise and detoxify a variety of anticancer drugs. McFadyen, et al. in Biochem Pharmacol. 2001, Jul. 15; 62(2): 207-12 demonstrated a significant decrease in the sensitivity of docetaxel in cells expressing CYP1B1 as compared with non-CYP1B1 expressing cells. This finding indicates that the presence of CYP1B1 in cells may decrease their sensitivity to some cytotoxic drugs. CYP1B1 activated pro-drugs may therefore be useful for the treatment of cancers whose drug resistance is mediated by CYP1B1.
WO-A-03/028713 discloses 3,4-methylenedioxy chalcones for use in the treatment of proliferative conditions, which 3,4-methylenedioxy chalcones exhibit such cytotoxicity in CYP1B1 expressing cells. According to WO-A-03/028713, such substituted chalcones may be represented by formula (A):

wherein:
each of RB2, RB3, RB4 and RB5 is independently —H, —OH or —OMe;
each of R1 and R2 is independently —H, optionally substituted C1-4 alkyl or optionally substituted C5-20 aryl;
RA3 is —H, —OH, —OC(═O)RE, —OS(═O)2OH or —OP(═O)(OH)2; and
RE is —H, optionally substituted C1-6 alkyl, optionally substituted C3-20 heterocyclyl or optionally substituted C5-20 aryl.